Identification of a gut microbiota member that ameliorates DSS-induced colitis in intestinal barrier enhanced Dusp6-deficient mice

• Published in: Cell reports (Cambridge) Vol. 37; no. 8; p. 110016
• Main Authors: Chang, Cherng-Shyang, Liao, Yi-Chu, Huang, Chih-Ting, Lin, Chiao-Mei, Cheung, Chantal Hoi Yin, Ruan, Jhen-Wei, Yu, Wen-Hsuan, Tsai, Yi-Ting, Lin, I-Jung, Huang, Chien-Hsun, Liou, Jong-Shian, Chou, Ya-Hsien, Chien, Hung-Jen, Chuang, Hsiao-Li, Juan, Hsueh-Fen, Huang, Hsuan-Cheng, Chan, Hong-Lin, Liao, Yu-Chieh, Tang, Shiue-Cheng, Su, Yu-Wen, Tan, Tse-Hua, Bäumler, Andreas J., Kao, Cheng-Yuan
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 23.11.2021
• Subjects: Animals; barrier integrity; Caco-2 Cells; Colitis - microbiology; Colitis - prevention & control; Colon - metabolism; Dextran Sulfate - pharmacology; Disease Models, Animal; Dual Specificity Phosphatase 6 - deficiency; Dual Specificity Phosphatase 6 - genetics; Dual Specificity Phosphatase 6 - metabolism; DUSP6; Dysbiosis - metabolism; Epithelial Cells - metabolism; experimental colitis; Feces; Female; Gastrointestinal Microbiome - physiology; gut microbiota; Humans; Intestinal Mucosa - microbiology; leaky gut; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; RNA, Ribosomal, 16S - metabolism; experimental colitis; barrier integrity; leaky gut; gut microbiota; DUSP6
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2021.110016

Strengthening the gut epithelial barrier is a potential strategy for management of gut microbiota-associated illnesses. Here, we demonstrate that dual-specificity phosphatase 6 (Dusp6) knockout enhances baseline colon barrier integrity and ameliorates dextran sulfate sodium (DSS)-induced colonic injury. DUSP6 mutation in Caco-2 cells enhances the epithelial feature and increases mitochondrial oxygen consumption, accompanied by altered glucose metabolism and decreased glycolysis. We find that Dusp6-knockout mice are more resistant to DSS-induced dysbiosis, and the cohousing and fecal microbiota transplantation experiments show that the gut/fecal microbiota derived from Dusp6-knockout mice also confers protection against colitis. Further culturomics and mono-colonialization experiments show that one gut microbiota member in the genus Duncaniella confers host protection from DSS-induced injury. We identify Dusp6 deficiency as beneficial for shaping the gut microbiota eubiosis necessary to protect against gut barrier-related diseases. [Display omitted] •Dusp6 deficiency protects against DSS-induced colitis in mice•Dusp6 knockout induces tight junction- and microvilli-associated gene expression•Dusp6 knockout results in elevation of mitochondrial oxygen consumption•A potential anti-colitis bacterium, NHRI-C1-K-H-1-87, is found in Dusp6-knockout mice Chang et al. report that Dusp6 deficiency strengthens the junctions and extends the microvilli, thereby enhancing colonic barrier integrity. Dusp6 deficiency also promotes glucose-to-lipid metabolic switch and elevates mitochondrial oxygen consumption, thereby maintaining the anaerobic state for preserving obligatory bacteria. An anti-colitis anaerobe, NHRI-C1-K-H-1-87, is identified in Dusp6-knockout mice.